A number of protein fusion toxins, composed of the diphtheria toxin (DT) toxophore and a targeting ligand, have been assembled and tested in Phase I clinical trials for the treatment of leukemias. To date, the only FDA approved protein fusion toxin is ONTAK. ONTAK is a DT, interleukin-2 receptor-targeted fusion toxin used to treat persistent or recurrent, cutaneous T-cell lymphoma. Sales of this drug range between $30 and $40M annually. DT-based protein fusion toxins targeting the interleukin-3 (IL-3) receptor have produced encouraging early clinical results. The goals of this Phase I proposal are to create a DT-IL3 fusion toxin, using a DT toxophore that has been modified to reduce potential for induction of vascular leak, that is as potent as the existing DT-IL3 fusion toxin. Vascular leakage in humans is a common side effect of fusion toxin therapy and can inhibit development of this class of therapeutic agent. A reduced side effect profilethe chances of a DT-IL3 toxin becoming available to treat patients with AML. [unreadable] [unreadable] [unreadable] reat AML. PUBLIC HEALTH RELEVANCE: This project seeks to determine if a DT-IL3 fusion toxin with reduce VLS profile can developed. This fusion toxin could provide a wider therapeutic window and thereby enhance [unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable][unreadable]